A Side-by-Side Comparison of Wildtype and Variant Melanocortin 1 Receptor Signaling with Emphasis on Protection against Oxidative Damage to DNA

Author:

Cerdido Sonia12ORCID,Sánchez-Beltrán José12ORCID,Lambertos Ana12ORCID,Abrisqueta Marta12ORCID,Padilla Lidia1ORCID,Herraiz Cecilia12ORCID,Olivares Conchi12ORCID,Jiménez-Cervantes Celia12ORCID,García-Borrón José C.12ORCID

Affiliation:

1. Department of Biochemistry, Molecular Biology and Immunology, School of Medicine, University of Murcia, 30120 Murcia, Spain

2. Instituto Murciano de Investigación Biosanitaria IMIB-LAIB, El Palmar, 30120 Murcia, Spain

Abstract

Common variants of the MC1R gene coding the α-melanocyte stimulating hormone receptor are associated with light skin, poor tanning, blond or red hair, and increased melanoma risk, due to pigment-dependent and -independent effects. This complex phenotype is usually attributed to impaired activation of cAMP signaling. However, several MC1R variants show significant residual coupling to cAMP and efficiently activate mitogenic extracellular signal-regulated kinase 1 and 2 (ERK1/2) signaling. Yet, residual signaling and the key actions of wildtype and variant MC1R have never been assessed under strictly comparable conditions in melanocytic cells of identical genetic background. We devised a strategy based on CRISPR-Cas9 knockout of endogenous MC1R in a human melanoma cell line wildtype for BRAF, NRAS and NF1, followed by reconstitution with epitope-labeled MC1R constructs, and functional analysis of clones expressing comparable levels of wildtype, R151C or D294H MC1R. The proliferation rate, shape, adhesion, motility and sensitivity to oxidative DNA damage were compared. The R151C and D294H RHC variants displayed impaired cAMP signaling, intracellular stability similar to the wildtype, triggered ERK1/2 activation as effectively as the wildtype, and afforded partial protection against oxidative DNA damage, although less efficiently than the wildtype. Therefore, common melanoma-associated MC1R variants display biased signaling and significant genoprotective activity.

Funder

Instituto de Salud Carlos III

European Union

predoctoral fellowship from the University of Murcia

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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